Membrane disruption by antimicrobial fatty acids releases low-molecular-weight proteins from Staphylococcus aureus.

ABSTRACT

The skin represents an important barrier for pathogens and is known to produce fatty acids that are toxic toward gram-positive bacteria. A screen of fatty acids as growth inhibitors of Staphylococcus aureus revealed structure-specific antibacterial activity. Fatty acids like oleate (181Δ9) were nontoxic, whereas palmitoleate (161Δ9) was a potent growth inhibitor. Cells treated with 161Δ9 exhibited rapid membrane depolarization, the disruption of all major branches of macromolecular synthesis, and the release of solutes and low-molecular-weight proteins into the medium. Other cytotoxic lipids, such as glycerol ethers, sphingosine, and acyl-amines blocked growth by the same mechanisms. Nontoxic 181Δ9 was used for phospholipid synthesis, whereas toxic 161Δ9 was not and required elongation to 181Δ11 prior to incorporation. However, blocking fatty acid metabolism using inhibitors to prevent acyl-acyl carrier protein formation or glycerol-phosphate acyltransferase activity did not increase the toxicity of 181Δ9, indicating that inefficient metabolism did not play a determinant role in fatty acid toxicity. Nontoxic 181Δ9 was as toxic as 161Δ9 in a strain lacking wall teichoic acids and led to growth arrest and enhanced release of intracellular contents. Thus, wall teichoic acids contribute to the structure-specific antimicrobial effects of unsaturated fatty acids. The ability of poorly metabolized 161 isomers to penetrate the cell wall defenses is a weakness that has been exploited by the innate immune system to combat S. aureus.